Cerebrotendinous Xanthomatosis

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31.1 Clinical Features

and Laboratory Investigations Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disorder with an autosomal recessive mode of inheritance. Prolonged neonatal cholestatic jaundice is common (“hepatitis of infancy”). Most patients are of borderline or low intelligence from the beginning and their school performance is poor.

Chronic, intractable, and unexplained diarrhea is present in about 50% of the affected children. The more specific clinical manifestations usually appear in late childhood or early adolescence, or even later. The most commonly noted early manifestations of the disease include cataracts and xanthomas of tendons, especially the Achilles tendons, but also the tendons of the quadriceps muscle, the triceps muscle, and the finger extensors. During the second or third decade, neurological problems gradually become manifest with signs of cerebellar ataxia, spastic paraparesis and tetraparesis, signs of dysfunction of the posterior columns, and signs of peripheral polyneuropathy.

Some patients have only signs of spinal cord dysfunction with pyramidal tract and dorsal column involvement. Tendon reflexes are generally hyperactive. Vi- bratory and position senses are diminished whereas the superficial sensory modalities remain relatively intact. Foot deformity, in particular pes cavus, is often noted. About 40% of the patients develop epilepsy with generalized tonic–clonic seizures. In most cases a decline of mental function occurs in the third decade, but there is wide diversity in the rapidity of the decline. Changes in personality and psychiatric problems may be present, varying from irritability, agitation, and aggressiveness to paranoid ideation, hallucinations, and catatonia. Premature atherosclerosis may lead to angina pectoris, myocardial infarc- tion, and cardiac failure. Less frequent complaints are pharyngeal and palatal myoclonus, tachylalia, mask- like facies, parkinsonism, bulbar and pseudobulbar paresis with dysphagia and dysphonia, visual loss due to optic atrophy, palpebral xanthelasmas, corneal lipoid arcus, generalized muscular wasting, bone fractures due to osteoporosis, impaired lung function due to pulmonary xanthomas, and signs of endocrine dysfunction. In untreated cases death usually occurs between the fourth and sixth decades.

The problem with the diagnosis of CTX is that there are no obligatory symptoms and that the devel-

opment of symptoms varies markedly in nature and degree of progression, even within one family. In particular in the absence of the typical tendon xanthomas, the diagnosis can be easily missed.

Laboratory investigations reveal normal or only moderately elevated serum cholesterol but a markedly increased level of serum cholestanol. CSF protein may be increased. CSF cholestanol levels are elevated.

Low serum levels of 25-hydroxy vitamin D3and 24,25- dihydroxy vitamin D3may be found. The measure- ment of the serum cholestanol to cholesterol ratio has been advocated as a means of establishing the diagnosis, but elevated cholestanol and elevated cholestanol to cholesterol ratios are not very specific and can also be found in patients suffering from var- ious liver diseases. A preferable method for establishing the diagnosis is to demonstrate the presence of abnormal bile alcohols in the urine. The diagnosis can be confirmed by demonstrating lack of 27-hydroxylase activity in cultured fibroblasts and by DNA techniques.

X-ray examination may reveal swelling of the Achilles tendons and, less frequently, of the tendons of the hamstrings, quadriceps, and finger extensors.

Calcification of these soft tissue masses may be seen.

Motor and sensory nerve conduction is often slowed.

Evoked potentials, in particular SSEPs, are as a rule delayed. EEG shows diffuse slowing of background activity with poorly organized theta and delta waves.

Carriers of CTX can be identified by observing an abnormal increase in bile alcohols in their urine after administration of cholestyramine, a drug that leads to intestinal loss of bile acids and as a consequence to increased endogenous synthesis. Normal control per- sons fail to produce the unusual bile alcohols. Carrier detection can also be performed by analysis of 27-hydroxylase activity in cultured fibroblasts or by DNA techniques. Prenatal diagnosis is possible using the same techniques.

31.2 Pathology

On external examination of the brain, mild atrophy is found, especially of the cerebellum. Sometimes xanthomas are seen in the choroid plexus.

On microscopic examination, the cerebral cortex and hemispheric white matter usually appear normal.

Sometimes gliosis and perivascular collections of

Cerebrotendinous Xanthomatosis

Chapter 31

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large mononuclear cells with foamy cytoplasm are found. Occasionally, prominent loss of myelin and axons may be found at the level of the corona radiata, periventricular white matter, and globus pallidus.

Mononuclear cells with foamy cytoplasm may be present in the basal nuclei and thalamus. The globus pallidus especially may contain large mononuclear cells with foamy cytoplasm, accompanied by demyelination of the fibers of the ansa lenticularis as they pass through the internal capsule. The optic nerves and tracts may exhibit loss of myelin and axons associat- ed with fibrillary gliosis and presence of perivascular lipid-laden mononuclear cells.

The most conspicuous abnormalities are found in the cerebellum. Xanthomatous tissue sometimes re- places most of the white matter. On microscopic examination extensive loss of myelin and axons is seen within the cerebellar white matter, with most severe involvement of the outflow tracts of the dentate nucleus and the superior cerebellar peduncles. In the affected areas many small and large cystic spaces and needle-like clefts are present. Large quantities of neutral fat accumulate within large mononuclear cells with foamy cytoplasm in the cysts and in perivascular spaces. The needle-shaped clefts contain crystalline deposits with staining properties of sterols.

The crystalline deposits are surrounded by inflam- matory cells and reactive multinucleated foreign- body giant cells. These cells represent the tissue reac- tion to deposition of sterols. There may be extensive loss of Purkinje cells and granule cells and destruc- tion of the dentate and fastigial nuclei. Particularly in the dentate nucleus, severe neuronal loss may be found with presence of clefts containing crystalline lipid deposits, as well as reactive astrocytosis, focal calcification, and deposition of hemosiderin pigment.

In the brain stem the pyramidal tracts, medial lemniscus, transverse pontine fibers, and superior cerebellar peduncles are involved. At the higher levels of the brain stem, in particular in the red nucleus and substantia nigra, deposits of neutral lipids and crystalline sterols are present. Gray matter changes in the brain stem include loss of neurons, particularly in the inferior olives and other nuclei. In the spinal cord the pyramidal tracts and posterior columns demonstrate loss of myelin sheaths and axons.

In the peripheral nerves extensive axonal degeneration is found. There may be additional signs of seg- mental demyelination and remyelination with onion bulb formation. Histological examination of muscle tissue discloses signs of denervation and reinnerva- tion with type grouping. On electron microscopy, large aggregates of mitochondria are seen, mainly in the subsarcolemmal region. The mitochondria show mild morphological abnormalities such as increased size and irregular cristae.

Microscopic examination of Achilles tendon xanthomas reveals islets of mononuclear cells with foamy cytoplasm and clefts filled with crystalloid material surrounded by multinucleated giant cells. The clefts are scattered in fan-shaped clusters without any rela- tion to blood vessels. Under polarized light birefrin- gence of the clefts is shown, suggesting presence of sterols. The cells filled with neutral fat are mainly present around blood vessels but also throughout the tissue.

Similar xanthomatous tissue can be found in the lungs and bones. In liver tissue fatty lipofuscin-like pigment granules have been reported in hepatocytes and Kupffer cells. Crystals are found in the cytoplasm of hepatocytes. Mitochondria are hypertrophied and peroxisomes are increased in size and number. Pre- mature atherosclerosis of coronary arteries can be found.

31.3 Chemical Pathology

In CTX patients the lipids stored in the brain and in xanthomas consist of free and esterified cholestanol and cholesterol. Free cholestanol is found not only in the evidently affected areas of the brain, but also in areas which appear normal on histological examination. Cholestanol is found in myelin and also in all other membrane structures in the brain, including cell membranes and membranes of subcellular structures. The concentration of unesterified cholesterol is normal or only slightly increased. In demyelinated areas the concentrations of esterified cholestanol and cholesterol are elevated. Concentrations of cholesterol esters are nonspecifically elevated in many actively demyelinating disorders, but esterified cholestanol is not present in any of these disorders.

31.4 Pathogenetic Considerations

In CTX the basic defect is located in the mitochon- drial enzyme 27-hydroxylase. This enzyme catalyzes the initial steps in the side-chain cleavage of sterols.

The enzyme hydroxylates a spectrum of sterol sub- strates, including cholesterol and vitamin D3. The sterol 27-hydroxylase gene, CYP27, is located on the distal portion of the long arm of chromosome 2 (2q35). Many different mutations have been identified. There is no clear correlation between genotype and phenotype.

The most important pathway for the metabolism and excretion of cholesterol in humans is the formation of bile acids. The two major bile acids, cholic acid and chenodeoxycholic acid, are formed in the liver and secreted in bile into the intestine. The enzymes involved in modifying the steroid nucleus of choles-

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terol are mainly located in the endoplasmic reticulum and the cytosol. The enzymes involved in the side- chain degradation are mainly located in mitochondria and peroxisomes. The major pathway for side- chain cleavage is the 27-hydroxylase pathway.

Deficient activity of 27-hydroxylase results in a defect in bile acid biosynthesis. The formation of normal bile acids, in particular chenodeoxycholic acid, is reduced. Large amounts of unusual C27 bile alcohols are excreted in bile, feces, and urine. As bile acids are involved in a feedback regulation of the hepatic cholesterol production, the decrease in bile acids leads to enhanced cholesterol production and excessive production of bile alcohols.

Cholestanol is the 5a-dihydro derivative of choles- terol. It normally represents about 0.1–0.3% of cholesterol in tissues and plasma. In CTX cholestanol is increased 10- to 100-fold, so that it accounts for 2% of plasma and tissue sterols with even greater enrich- ment in the brain (20–50%), tendon xanthomas (10%), and bile (10%). There is evidence that the increased synthesis of cholestanol is caused by the increased utilization of bile intermediates as precursors for cholestanol. The bile intermediates accumulating in CTX may be shunted into the cholestanol pathway.

Like cholesterol, cholestanol is transported by low- density lipoproteins (LDL) and high-density lipoproteins (HDL). Despite the enhanced production of both sterols, plasma LDL concentrations are low and HDL cholesterol levels are also diminished. The role of LDL is to transport cholesterol from the liver to peripheral tissues. LDL turnover is exceedingly rapid in CTX. The catabolism of LDL by the augmented expression of LDL receptors is sufficiently great to maintain low plasma concentrations, despite enhanced cholesterol production. The role of HDL is to transport cholesterol from peripheral tissues to the liver. HDL cholesterol levels are subnormal in many CTX patients. This may account for the accumulation of tissue sterols in atheromas and xanthomas by hin- dering reverse sterol transport.

Neurophysiology and histopathology suggest that axonal degeneration is primary in CTX, although there may also be a component of primary myelin loss. The precise pathophysiological mechanisms are unclear. Evidently, the deposition of cholestanol and cholesterol in the nervous system and the replace- ment of cholesterol by cholestanol must be important in the development of the nervous tissue damage.

There is evidence that there is a subtle defect in the blood–brain barrier in CTX, probably caused by the accumulating toxic metabolites. The defect in the blood–brain barrier may be important in the accre- tion of cholestanol and cholesterol within the CNS. In CTX the fractional clearance of LDL is enhanced, most likely due to an increased activity of hepatic LDL receptors. LDL receptors within the blood–brain

barrier may be up-regulated as well, in this way con- tributing to the influx of sterols into the CNS.

31.5 Therapy

Treatment in CTX aims at breaking the vicious circle of defective endogenous bile acid synthesis leading to absence of negative feedback, which in turn leads to increased production of cholesterol, abnormal bile alcohols, and cholestanol. Treatment with oral bile acids, in particular chenodeoxycholic acid, repairs the negative feedback and leads to decreased production of cholesterol, cholestanol, and abnormal bile alcohols. Assessment of serum cholestanol and uri- nary bile alcohols can be used to monitor treatment.

Once treatment starts, the diarrhea ceases. The progression of CNS damage is retarded or halted. Pa- tients receiving therapy with chenodeoxycholic acid have been reported to show reversal of their neurological disability, with clearing of dementia and im- proved motor function. There is also evidence of im- proved results of paraclinical tests, such as nerve conduction velocity, evoked responses, EEG, and CT.

Combined treatment with chenodeoxycholic acid and 3-hydroxy-3-methylglutaryl coenzyme A reduc- tase inhibitors such as simvastatin, lovastatin, or pravastatin – inhibitors of cholesterol synthesis, leads to a more pronounced reduction of cholesterol and cholestanol than treatment with chenodeoxycholic acid alone. Their long-term clinical efficacy of this combined treatment has still to be proven.

Some patients experience a more marked improve- ment than others. As the effects of therapy depend largely on the extent of irreversible structural damage to nervous tissue, early diagnosis and early treatment are important. If the disease is detected in early childhood, treatment of the patient not yet clinically affected can prevent occurrence of complaints. It is a treatment for life.

31.6 Magnetic Resonance Imaging

CT scan of the brain has been reported to show cerebellar hypodensity and in some cases also moderate hypodensity of cerebral hemispheric white matter.

Increased density may be seen in the area of the dentate nucleus, corresponding to hemosiderin and calcium deposition in histopathology.

The most important and earliest MRI abnormalities are noted in the cerebellum. On T2-weighted images the dentate nucleus and cerebellar hemispheric white matter have a high signal intensity (Figs. 31.1 and 31.2). The cerebellar foliae are prominent, indica- tive of atrophy (Fig. 31.2). In some patients, the dentate nucleus has a low signal intensity on T2-weighted

Chapter 31 Cerebrotendinous Xanthomatosis 254

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images (Fig. 31.2). In exceptional cases, the cerebellar white matter lesions are surrounded by a rim of markedly low signal intensity (Fig. 31.4). The low signal on T2-weighted images reflects the presence of macroscopic xanthomas or calcium and hemosiderin deposits. Symmetrical lesions are often present in the corticospinal tracts and medial lemniscus in the brain stem (Figs. 31.1 and 31.2). In some patients, the transverse pontine fibers contain signal abnormalities. Involvement of the inferior olives may occur.

In the supratentorial region, ill-defined slight signal changes are seen in the periventricular region in most patients, blending with the normal white matter without a sharp demarcation between the two (Figs. 31.1–31.3). They have a symmetrical distribu- tion. These abnormalities may be confluent or patchy.

U fibers and corpus callosum are spared. Slight en- largement of the ventricles and subarachnoid spaces may be seen. In a few patients, focal round or ovoid masses with low signal intensity on T2-weighted images are noted within the ventricles, probably reflect-

ing the presence of xanthomas within the choroid plexus (Fig. 31.4). T2-weighted images often reveal bilateral high-signal-intensity lesions in the globus pallidus and the adjacent part of the internal capsule, in the area of the ansa lenticularis (Fig. 31.3). The globus pallidus may have a low signal intensity, probably related to the high lipid content (Fig. 31.2).

Within the spinal cord, the lateral and dorsal columns may have a high signal intensity on T2- weighted images (Fig. 31.5). Lipid deposits in the Achilles tendon can be visualized (Fig. 31.6).

The full-blown MRI pattern of CTX, consisting of the typical cerebellar abnormalities with high-signal- intensity changes within the white matter and a low signal intensity of the dentate nucleus on T2-weighted images, has a high diagnostic value. When only high- signal-intensity lesions are present in the cerebellar (and also cerebral) white matter, other diagnoses should be considered, including adrenomyeloneu- ropathy and Refsum disease.

Fig. 31.1. The T2-weighted images in this 40-year-old male CTX patient reveal signal abnormalities in the dentate nucleus and medial lemniscus in the midbrain. In addition, there are diffuse, ill-defined slight signal abnormalities in the cerebral

white matter. Courtesy of Dr. F. Barkhof, Department of Radiol- ogy, VU University Medical Center, Amsterdam, and Dr. A. Ver- rips, Department of Pediatric Neurology, University Medical Center Nijmegen, The Netherlands

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Fig. 31.2. The T2-weighted images in this 48-year-old female CTX patient reveal diffuse, ill-defined slight signal abnormalities within the cerebral white matter, sparing the corpus callosum, and some cerebral atrophy.The globus pallidus has a low signal intensity.The pyramidal tracts in the brain stem, the medial lemniscus at the level of the pons, the cerebellar hemi-

spheric white matter, and the hilus of the dentate nucleus dis- play an elevated signal intensity. The dentate nucleus stands out as dark. Courtesy of Dr. F. Barkhof, Department of Radio- logy, VU University Medical Center, Amsterdam, and Dr. A. Ver- rips, Department of Pediatric Neurology, University Medical Center Nijmegen, The Netherlands

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Fig. 31.3. Male, 38 years of age, with CTX.The T2-weighted images show a diffuse slight signal abnormality within the cerebral white matter.There are signal abnormalities in the medial globus pallidus and adjacent part of the posterior limb of the internal capsule, the pyramidal tracts, and medial lemniscus in the midbrain. The dentate nucleus has a low signal, whereas

the hilus of the dentate nucleus and cerebellar hemispheric white matter have a high signal. Note the cerebellar atrophy.

Courtesy of Dr. F. Barkhof, Department of Radiology,VU Univer- sity Medical Center, Amsterdam, and Dr. A.Verrips, Department of Pediatric Neurology, University Medical Center Nijmegen, The Netherlands

Fig. 31.4. Female, 43 years of age, with CTX. On the T2-weighted image on the left, the cerebellar white matter has a high signal intensity surrounded by a rim of very low signal intensity.

The moderately T2-weighted image on the right shows the involvement of the corticospinal tracts in the midbrain. Note the round masses with low signal intensity in the choroid plexus of the lateral ventricles. From Fiorelli et al. (1990), with permission

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Fig. 31.5. Spinal images in a 41-year- old woman with CTX. The sagittal mildly T2-weighted images reveal mild signal abnormalities in the spinal cord over its entire length. Courtesy of Dr. F. Barkhof, Department of Radio- logy, VU University Medical Center, Amsterdam, and Dr. A. Verrips, Depart- ment of Pediatric Neurology, Uni- versity Medical Center Nijmegen, The Netherlands

Fig. 31.6. The T1-weighted images show the typical swelling of the Achilles tendon in two CTX patients (arrows). Courtesy of Dr. F. Barkhof, Department of Radiology, VU Uni- versity Medical Center, Amsterdam, and Dr. A. Verrips, Department of Pediatric Neurology, University Medical Center Nijmegen, The Netherlands